The goal of this project is to determine the effects in breast cancer cells of inhibiting Ras-processing with a farnesyl transferase inhibitor (FTI). We have shown that FTIs arrest and kill cells by p53-dependent and independent mechanisms and synergize with both taxanes and inhibitors of EGF receptor. Our goals are: To identify the key franesylated protein targets of the drug; To further elucidate the mechanisms of FTI induction of p21 in cells containing wild type p53 and of endoreduplication and apoptosis in cells lacking p53 function; To use the knowledge we have accumulated to test the efficacy of FTI as treatment of advanced breast cancer. We have also determined that the ansamycin antibiotics bind to Hsp90 and cause degradation of several specific classes of protein required for cancer cell growth and survival. We are now involved in developing clinical applications of this work, including a phase I trial of a geldanamycin analog. Lead compounds that selectively degrade HER- kinases and estrogen receptor have been identified and are being characterized.